Hajera Amatullah1,2, Yuexin Shan1, Brittany L Beauchamp3, Patricia L Gali1, Sahil Gupta1,4, Tatiana Maron-Gutierrez5,6, Edwin R Speck1, Alison E Fox-Robichaud7, Jennifer L Y Tsang1,8, Shirley H J Mei9, Tak W Mak10, Patricia R M Rocco6, John W Semple1, Haibo Zhang1, Pingzhao Hu11, John C Marshall1, Duncan J Stewart9, Mary-Ellen Harper3, Patricia C Liaw8, W Conrad Liles12, Claudia C Dos Santos1,4. 1. 1 The Keenan Research Centre for Biomedical Science of the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada. 2. 2 Department of Physiology, Faculty of Medicine, and. 3. 4 Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada. 4. 3 Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, and. 5. 9 Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada. 6. 5 Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil. 7. 6 Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. 8. 7 Thrombosis and Atherosclerosis Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada. 9. 8 Department of Medicine, McMaster University, Hamilton (Niagara Campus), Ontario, Canada. 10. 10 Department of Medical Biophysics and Immunology, The Campbell Family Institute for Breast Cancer Research at Princess Margaret Hospital, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada. 11. 11 Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada; and. 12. 12 Department of Medicine, University of Washington, Seattle, Washington.
Abstract
RATIONALE: Effective and rapid bacterial clearance is a fundamental determinant of outcomes in sepsis. DJ-1 is a well-established reactive oxygen species (ROS) scavenger. OBJECTIVES: Because cellular ROS status is pivotal to inflammation and bacterial killing, we determined the role of DJ-1 in bacterial sepsis. METHODS: We used cell and murine models with gain- and loss-of-function experiments, plasma, and cells from patients with sepsis. MEASUREMENTS AND MAIN RESULTS: Stimulation of bone marrow-derived macrophages (BMMs) with endotoxin resulted in increased DJ-1 mRNA and protein expression. Cellular and mitochondrial ROS was increased in DJ-1-deficient (-/-) BMMs compared with wild-type. In a clinically relevant model of polymicrobial sepsis (cecal ligation and puncture), DJ-1-/- mice had improved survival and bacterial clearance. DJ-1-/- macrophages exhibited enhanced phagocytosis and bactericidal activity in vitro, and adoptive transfer of DJ-1-/- bone marrow-derived mononuclear cells rescued wild-type mice from cecal ligation and puncture-induced mortality. In stimulated BMMs, DJ-1 inhibited ROS production by binding to p47phox, a critical component of the NADPH oxidase complex, disrupting the complex and facilitating Nox2 (gp91phox) ubiquitination and degradation. Knocking down DJ-1 (siRNA) in THP-1 (human monocytic cell line) and polymorphonuclear cells from patients with sepsis enhanced bacterial killing and respiratory burst. DJ-1 protein levels were elevated in plasma from patients with sepsis. Higher levels of circulating DJ-1 were associated with increased organ failure and death. CONCLUSIONS: These novel findings reveal DJ-1 impairs optimal ROS production for bacterial killing with important implications for host survival in sepsis.
RATIONALE: Effective and rapid bacterial clearance is a fundamental determinant of outcomes in sepsis. DJ-1 is a well-established reactive oxygen species (ROS) scavenger. OBJECTIVES: Because cellular ROS status is pivotal to inflammation and bacterial killing, we determined the role of DJ-1 in bacterial sepsis. METHODS: We used cell and murine models with gain- and loss-of-function experiments, plasma, and cells from patients with sepsis. MEASUREMENTS AND MAIN RESULTS: Stimulation of bone marrow-derived macrophages (BMMs) with endotoxin resulted in increased DJ-1 mRNA and protein expression. Cellular and mitochondrial ROS was increased in DJ-1-deficient (-/-) BMMs compared with wild-type. In a clinically relevant model of polymicrobial sepsis (cecal ligation and puncture), DJ-1-/- mice had improved survival and bacterial clearance. DJ-1-/- macrophages exhibited enhanced phagocytosis and bactericidal activity in vitro, and adoptive transfer of DJ-1-/- bone marrow-derived mononuclear cells rescued wild-type mice from cecal ligation and puncture-induced mortality. In stimulated BMMs, DJ-1 inhibited ROS production by binding to p47phox, a critical component of the NADPH oxidase complex, disrupting the complex and facilitating Nox2 (gp91phox) ubiquitination and degradation. Knocking down DJ-1 (siRNA) in THP-1 (human monocytic cell line) and polymorphonuclear cells from patients with sepsis enhanced bacterial killing and respiratory burst. DJ-1 protein levels were elevated in plasma from patients with sepsis. Higher levels of circulating DJ-1 were associated with increased organ failure and death. CONCLUSIONS: These novel findings reveal DJ-1 impairs optimal ROS production for bacterial killing with important implications for host survival in sepsis.
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